Patent GB-791914-A (GB)
Title: Manufacture of compounds of the suprarenal cortex hormone series
IPC: C07J75/00
Filed: 1954-06-11
Abstract: The invention comprises 20-oxopregnane compounds unsubstituted in the 17-position, containing in the 3-position a free or functionally converted hydroxy or oxo group, in the 16-position a free or functionally converted hydroxy group and in the 21-position a free or acylated hydroxy group, and having, if desired, a double-bond involving carbon atom 5, and a process for the manufacture of 20-oxopregnane compounds containing the specified substituents in the 3-, 16- and 21-positions wherein compounds of the pregnane series containing in the 3-position a free or functionally converted hydroxy or oxo group, in the 16-position an esterified or etherified hydroxy group, in the 20-position an oxo group and in the 21-position at least one hydrogen atom are reacted with lead tetracylates, and, if desired, functionally converted hydroxy or oxo groups are liberated and/or free hydroxy groups are functionally converted or oxidized to keto groups and/or a double bond is introduced in a -position to a free 3-oxo group.  A liberated hydroxy group, particularly in the 21-position, may subsequently be selectively esterified or etherified, e.g. by reaction with acid chlorides or anhydrides or isopropenyl acylates (if desired in approximately equivalent amounts and under very mild reaction conditions) or with carbohydrates.  The starting materials may be further unsaturated or further substituted, e.g. carbon atom 21 may carry, in addition to at least one hydrogen atom, a carboxyl, carbalkoxy or oxalyl group, or there may be present free or substituted hydroxy or oxo groups, epoxy groups or halogen atoms in, for example, the 2-, 4-, 5-, 6-, 7-, 11-, 12-, 14-, 15-, 17- or 19-position.  In examples: (1) D 5(6)-3b  : 16b -diacetoxy - 17a  - hydroxypregnen - 20 - one is treated with lead tetracetate in glacial acetic acid to produce D 5(6)-3b  : 16b  : 21-triacetoxy-17a -hydroxypregnen-20-one; (2) D 4(5)-16b -acetoxy - 17a  - hydroxypregnene - 3 : 20 - dione similarly gives D 4(5)-16b  : 21-diacetoxy-17a -hydroxypregnene-3 : 20-dione, in which the acetoxy groups may be hydrolysed with aqueous methanolic sodium methoxide solution; (3) D 5:6 - 3b  - formyloxy - 16a  - acetoxy - 20 - oxopregnene similarly yields D 5:6-3b -formyloxy-16a  : 21-diacetoxy-20-oxopregnene, in which the 3b -formyloxy group is selectively hydrolysed with aqueous potassium bicarbonate solution, the double bond is protected with bromine, the 3b -hydroxy group is oxidized to a keto group by means of chromium trioxide in acetic acid, the bromine is split off with chromous chloride to produce a D 4(5)-double bond, the two acetoxy groups are hydrolysed with an enriched active cholinesterase fraction in aqueous sodium acetate solution and the 21-hydroxy group reesterified with acetic anhydride and pyridine in benzene, forming finally D 4(5)-3 : 20-dioxo-16a  - hydroxy - 21 - acetoxypregnene; if the starting material is replaced by the corresponding 16a -benzyloxy compound there is obtained D 5(6) - 3b  - formyloxy - 16a  - benzyloxy - 21 - acetoxy - 20 - oxopregnene, in which the benzyloxy group can be converted to hydroxy by catalytic hydrogenation.  Additional lead tetracylates are listed, whilst further functionally converted hydroxy and oxo group specified include: alkoxy and aryloxy groups, ether groups with heterocyclic residues, and ester groups with the residues of benzyl- and diphenylmethyl-carbonic acids and methaneand p-toluene-sulphonic acids; ketals (including cyclic ketals), enol ethers and esters, enamines (e.g. of pyrrolidine) and hydrazones (e.g. semicarbazones). Starting materials.  D 5(6)-3b  : 16b -Diacetoxy-17a  - hydroxypregnen - 20 - one is prepared by the action of glacial acetic acid and sulphuric acid on the corresponding 16 : 17a -oxide or the oxide of the free 3b -hydroxy compound. D 4(5) - 16b  - Acetoxy - 17a - hydroxypregnene-3 : 20-dione is analogously prepared.  D 5(6)-3b -Formyloxy - 16a  - acetoxy - 20 - oxopregnene is prepared by hydrogenating the corresponding 16a -benzyloxy compound in the presence of palladium/charcoal and esterifying the resulting 16a -hydroxy group with acetic anhydride and pyridine.